Application of calcitonin for treating rheumatoid arthritis

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely rheumatology, and is applicable for preventing and treating rheumatoid arthritis in a patient. That is ensured by the oral administration of a therapeutically effective amount of calcitonin in the free form or in the form of a salt or a delivery agent specified in a group specified in N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), N-(10-[2- hydroxybenzoyl]amino)decanoic acid (SNAD), N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC) and their pharmaceutically acceptable salts.

EFFECT: oral introduction promotes improved absorption, more acceptable pharmacokinetic and pharmacodynamic profile and a smaller degree of calcitonin variability, as compared with the other methods of delivery that provides reduced chondrolysis.

8 cl, 2 dwg, 2 tbl, 4 ex

 

The present invention relates to a new use of calcitonin for the treatment of rheumatoid arthritis and the treatment and/or prevention of rheumatoid arthritis in mammals, especially in humans.

Calcitonin, for example, calcitonin salmon, eel (Asu 1-7) or person according to the present invention are long-chain polypeptide hormones, sekretiruemyi parafollicular cells of the thyroid gland of mammals, ultimobranchial glands of fishes and birds. Calcitonin is known as an effective inhibitor osteoclastic resorption of bone tissue, which includes the adherence of osteoclasts and enzymatic degradation in the bone tissue. In addition, it was found that intranasal calcitonin salmon affects juvenile idiopathic rheumatoid arthritis in humans (Siamopoulou A. and others, Calcif Tissue Int, 69, SS-30 (2001)) and prevents erosion and bone loss in rheumatoid arthritis in humans (Sileghem A., Annals of Rheumatic Diseases, 51, cc.761-764 (1992)). The degradation process associated with the synthesis of various proteases and metalloproteinases, activation of inactive proenzymes and inhibition of the active enzyme (Leloup G, J. Bone Miner. Res., 9, cc.891-902 (1994)). Found that calcitonin causes retraction of osteoclasts (M. Zheng. and others, .. Mole Pathol, 57, cc.105415 (1992)) and is influenced by at least several stages F. mentative process of bone resorption (Einhorn T.A. and others, Clin. Orthop., 262, cc.286-297 (1991)). Published several works devoted to the study of the effect of calcitonin on articular cartilage. Found that calcitonin in vitro stimulates the synthesis of proteoglycan and collagen in the epiphyseal cartilage in animals (Baxter and others, Endocrinology, 114, cc.1196-1202 (1984)), and furthermore, in rabbits and humans (Franchimont P, J. Clin, end Metab., 69, cc.259-266 (1989)).

In the present invention it has been unexpectedly found that oral administration of calcitonin, for example, calcitonin salmon, eel (Asu 1-7) or human, can be used for the prevention and treatment of rheumatoid arthritis in mammals, especially in humans.

Unexpectedly, it was found that at the specified oral administration of calcitonin observed enhanced effect compared with other routes of administration and, therefore, the oral method is the preferred method of introduction as a stable absorption, convenient and easy way deliver virtually pain-contributes to patients ' compliance with treatment compared with other delivery methods.

It was found that the oral administration of calcitonin unexpectedly observed improved absorption and more acceptable pharmacokinetic profile (FC profile) and a lower degree of variability.

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory out the immune disease where targets are primarily the synovial tissue. If the disease is not treated, it leads to disability and premature death. Worldwide, the disease develops in approximately 0.8% of the adult population, more common in women (3:1) and in most cases develops in childbearing age.

The defeat of the joints occurs at an early stage of development of rheumatoid arthritis, 30% of patients during the diagnosis of disease during x-ray examinations observed erosion of the bone, and within two years, this value increases to 60%. The diagnosis cannot be set on the basis of the results of a single laboratory test or procedure and it is recommended to use the seven diagnostic criteria, confirming the clinical manifestations and, consequently, the diagnosis depends on the doctor asked questions and identify early, often minor physical symptoms. Diagnostic criteria include a feeling of tightness in the morning, defeat arthritis of three or more joints, arthritis of hand joints, symmetric lesions of the joints, the presence of rheumatoid nodules, elevated rheumatoid factor in serum and radiographic changes. Many other factors, including a self-limiting viral disease once ivydene in a few weeks, mimic rheumatoid arthrit.

Rheumatoid arthritis is a disease characterized by inflammation and swelling of skeletal joints, primarily the small joints of the extremities, leading to erosion and destruction of cartilage and bone. The present invention can be used to inhibit, stop or even treatment of erosion and destruction of cartilage and bone and to reduce pain associated with rheumatoid arthritis.

In accordance with the present invention discoveries features:

1.1 a Method for preventing and/or treating rheumatoid arthritis in a patient in need of such treatment, which consists in the introduction indicated patient a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form in the form of a pharmaceutically acceptable oral delivery form, with a therapeutically effective amount of calcitonin administered orally in the form of a composition comprising calcitonin and agent for delivery of calcitonin.

1.2 a Method for preventing and/or treating rheumatoid arthritis in a patient in need of such treatment, which consists in the introduction indicated patient a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form, in the form of a pharmaceutically pickup is integral oral form, thus a therapeutically effective amount of calcitonin administered orally in the form of a composition comprising calcitonin in the composition of the conjugate with the polymer molecule.

1.3 Method of suppressing joint inflammation in a patient in need of such treatment, which consists in the introduction of oral indicated patient a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form, in the form of a pharmaceutically acceptable oral delivery form.

1.4 Method of suppressing the swelling of the skeletal joints of patients in need of such treatment, which consists in the introduction of oral indicated patient a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form, in the form of a pharmaceutically acceptable oral delivery form.

1.5 Method of suppression, suspension and even the treatment of erosion and destruction of cartilage and bone tissue in a patient in need of such treatment, which consists in the introduction of oral indicated patient a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form, in the form of a pharmaceutically acceptable oral delivery form.

1.6 Method of reducing pain associated with rheumatoid arthritis, in a patient in need of such cured and, which is the introduction of oral indicated patient a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form, in the form of a pharmaceutically acceptable oral delivery form.

1.7 the above-Described method, which consists in the joint introduction of a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form, in the form of a pharmaceutically acceptable oral delivery form and a second drug substance.

Suitable second drug substance include calcitonin different origin, such as calcitonin salmon calcitonin, eel (Asu 1-7) or human calcitonin analogue or derivative inhibitors SOH-2, for example lumiracoxib (Prexige®), celecoxib (Celebrex®), rofecoksib (Vioxx®), valdecoxib (Bextra®), etoricoxib (Arcoxia®), or a mixture of inhibitors of MOR-1 and MOR-2, for example, diclofenac, etanercept (Enbrel®), analgesics (e.g. aspirin, paracetamol), agents that form bone tissue, and agents against bone resorption.

1.8 the above-Described method, which consists in the joint introduction of a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form, in the form of a pharmaceutically acceptable oral delivery form and vtoro the drug substance, where is calcitonin salmon calcitonin, eel (Asu 1-7) or person, analogue or derivative of calcitonin in free form or in salt form.

1.9 the above-Described method, which consists in the joint introduction of a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form, in the form of a pharmaceutically acceptable oral delivery form and a second drug substance, which is an inhibitor SOH-2, for example lumiracoxib (Prexige®), celecoxib (Celebrex®), rofecoksib (Vioxx®), valdecoxib (Bextra®), etoricoxib (Arcoxia®) in free form or in salt form.

2. The above method, which is in the joint introduction of a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form, in the form of a pharmaceutically acceptable oral delivery form and a second drug substance, which is a mixture of inhibitors of MOR-1 and MOR-2, for example diclofenac in free form or in salt form.

2.1 the above method, which is in the joint introduction of a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form, in the form of a pharmaceutically acceptable oral delivery form and a second drug substance, which is an anesthetic agent (n is an example, aspirin, paracetamol) in free form or in salt form.

2.2 the above method, which is in the joint introduction of a therapeutically effective amount of calcitonin, e.g. calcitonin salmon in free form or in salt form, in the form of a pharmaceutically acceptable oral delivery form and a second drug substance, which is etanercept (Enbrel®) in free form or in salt form.

Etanercept (Enbrel®) is a dimer hybrid protein comprising a ligand-binding extracellular fragment of the receptor of tumor necrosis factor person (TNFR) MM 75 kDa. Such anti-TNF specifically binds with receptors of TNF and blocks its interaction with TNF receptors on the cell surface.

Another object of the present invention offers the preferred range of doses of calcitonin, for example, calcitonin salmon, which have shown efficacy and high tolerability, i.e. are safe when administered to patients. Preferred is the range from 0.4 to 2.5 mg of calcitonin salmon for the patient, for example, that the average person weighing approximately 70 kg is preferred dose of about 0.8 mg, for example from 0.6 to 1.2 mg. in Addition, the preferred dose is less than 1 mg, but more than 0.4 mg more is preferred dose is about 0.6-0.8 mg, for example 0,8 mg Most preferred is a dose of about 0.8 mg, for example from 0.8 to 1.2 mg, with the introduction of once daily to a patient in need of treatment. Pharmaceutical compositions comprising the above dose of the present invention suitable for oral administration. The treatment involves the introduction of one or two times daily, preferably once in the morning and once in the evening.

2.3 Method of prevention and/or treatment of rheumatoid arthritis in a patient in need of such treatment, which consists in the introduction of oral indicated patient a pharmaceutical composition comprising from 0.4 to 2.5 mg, preferably from 0.6 to 1.2 mg of calcitonin, e.g. calcitonin salmon.

2.4 Use of calcitonin, e.g. calcitonin salmon for obtaining a medicinal product intended for the treatment and/or prevention of rheumatoid arthritis, and specified calcitonin included in pharmaceutical compositions for oral administration comprising from 0.4 to 2.5 mg, preferably from 0.6 to 1.2 mg of calcitonin, e.g. calcitonin salmon.

2.5 Pharmaceutical composition for oral administration for the treatment and/or prevention of rheumatoid arthritis, comprising from 0.4 to 2.5 mg, preferably from 0.6 to 1.2 mg of calcitonin, e.g. calcitonin salmon.

The term "co-introduced the e" and so on, used in this context, means the administration of the selected therapeutic agents to a single patient, and means courses of treatment, in which the agents are not necessarily administered in the same way and/or at the same time.

In another embodiment, the present invention also available

2.6 Calcitonin, for example, calcitonin salmon, eel calcitonin (Asu 1-7) or person in the free form or in salt form in the form of a pharmaceutically acceptable form for oral administration designed for use in any of the ways described above in paragraph 1.1-2.3, or

2.7 Calcitonin, for example, calcitonin salmon, eel (Asu 1-7) or person in the free form or in salt form in the form of a pharmaceutically acceptable form for oral administration designed to obtain drugs for the treatment of diseases described above in paragraph 1.1-1.6 or

2.8 Pharmaceutical composition for use in the treatment of the diseases described above in paragraph 1.1-1.6, including calcitonin, for example, calcitonin salmon, eel (Asu 1-7) or person in the free form or in salt form in the form of a pharmaceutically acceptable form for oral administration in a mixture with one or more pharmaceutically acceptable diluents or carriers.

2.9 Pharmaceutical combination

a) a first agent which is calcite is h, for example, calcitonin salmon, eel (Asu 1-7) or person in the free form or in salt form in the form of a pharmaceutically acceptable form for oral administration and

b) joint agent chosen from the group comprising calcitonin salmon, eel (Asu 1-7) or person, analogue or derivative of calcitonin, inhibitors SOH-2, for example, lumiracoxib (Prexige®), celecoxib (Celebrex®), rofecoksib (Vioxx®), valdecoxib (Bextra®), etoricoxib (Arcoxia®), or a mixture of inhibitors of MOR-1 and MOR-2, for example, diclofenac, etanercept (Enbrel), analgesic agents (e.g. aspirin, paracetamol), agents, bone-forming, and agents against bone resorption, for example, above.

3. Set of components for the prevention and/or treatment of rheumatoid arthritis, including:

a) a first agent which is a calcitonin, e.g. calcitonin salmon, eel (Asu 1-7) or person in the free form or in salt form in the form of a pharmaceutically suitable form for oral administration and

b) joint agent chosen from the group comprising calcitonin salmon, eel (Asu 1-7) or person, analogue or derivative of calcitonin, inhibitors SOH-2, for example lumiracoxib (Prexige®), celecoxib (Celebrex®), rofecoksib (Vioxx®), valdecoxib (Bextra®), etoricoxib (Arcoxia®), or a mixture of inhibitors of MOR-1 and MOR-2, for example, diclofenac, etanercept (Enbrel®), analgesic the agents (aspirin, paracetamol, agents, bone-forming, and agents against bone resorption).

First of all, the present invention relates to a method for prevention or treatment of rheumatoid arthritis or related conditions, such as inflammatory diseases of the joints, swelling of skeletal joints, erosion and destruction of cartilage and bone tissue in a patient in need of such treatment, and this method is the introduction to a specified patient orally therapeutically effective amount of calcitonin, first of all, calcitonin salmon, eel (Asu 1-7) or, more preferably calcitonin salmon in free form or in salt form and the agent for delivery of calcitonin.

In another embodiment, the invention relates to a method of reducing pain associated with rheumatoid arthritis, in a patient in need of such treatment, which consists in the introduction of oral indicated patient a therapeutically effective amount of calcitonin in free form or in salt form, and agent for delivery of calcitonin.

In another embodiment, the present invention relates to a method for prevention or treatment of rheumatoid arthritis or related conditions in a patient in need of such treatment, which consists in the introduction of oral indicated patient a therapeutically effective the amount of calcitonin, first of all, calcitonin salmon, in free form or in salt form and the agent for delivery of calcitonin and agent for delivery, means a compound of the formula I

where

R1, R2, R3and R4independently mean hydrogen, -OH, -NR6R7, halogen, C1-C4alkyl or C1-C4alkoxy,

R5means substituted or unsubstituted With2-C16alkylene, substituted or unsubstituted With2-C16albaniles, substituted or unsubstituted With1-C12alkyl(aralen) or substituted or unsubstituted aryl(C1-C12alkylen), and

R6and R7independently mean hydrogen, oxygen, or C1-C4alkyl, its disodium salt, hydrate and alcohol solvate.

First of all the agent for delivery is chosen from the group consisting of 5-CNAC, SNAD, SNAC and their pharmaceutically acceptable salts, preferably from the group comprising disodium salt of 5-CNAC, disodium salt of SNAD and disodium salt of SNAC.

In another embodiment, the agent for delivery of the present invention is used in finely powdered form, preferably with an average particle size of less than 40, more preferably less than 20, even more preferably less than 10 microns.

In yet another embodiment, the present invention proposes a method that is centuries in the Denia oral therapeutically effective amount of calcitonin in the composition, including calcitonin in the composition of the conjugate with the polymer molecule.

In another embodiment proposes a method which consists in the introduction of oral therapeutically effective amount of calcitonin in standard dosage forms, including calcitonin, at least one pharmaceutically acceptable agent to reduce the pH, at least one amplifier, absorption and intersolubility floor.

First of all, the present invention relates to a method for prevention or treatment of rheumatoid arthritis or related conditions in a patient in need of such treatment, which consists in the introduction of oral indicated patient a therapeutically effective amount of calcitonin, first of all, calcitonin salmon, in free form or in salt form and the agent for delivery of calcitonin, with a therapeutically effective amount of calcitonin is from 0.4 mg to 2.5 mg for the patient, for example, a man weighing, for example, 70 kg, together with the agent for delivery of calcitonin. More preferably used in the method according to the present invention dose of about 0.8 mg, for example from 0.6 mg to 1.2 mg, even more preferably using doses less than 1 mg, but more than 0.4 mg, for example, a dose of from about 0.6 mg to 0.8 mg, for example, 0.8 mg first dose when listello 0.8 mg, for example, from 0.8 to 1.2 mg of the dose administered in the form of a single or multiple dosage forms, primarily once a day, or in another embodiment, two times a day.

In yet another embodiment, the present invention relates to the use of calcitonin to obtain drugs for oral administration, comprising a therapeutically effective amount of calcitonin, first of all, calcitonin salmon, eel (Asu 1-7) or, more preferably calcitonin salmon in free form or in salt form, and agent for delivery of calcitonin, intended for the prevention or treatment of rheumatoid arthritis in a patient in need of such treatment, and, above all, the agent for delivery mean compound of the formula I

where

R1, R2, R3and R4independently mean hydrogen, -OH, -NR6R7, halogen, C1-C4alkyl or C1-C4alkoxy,

R5means substituted or unsubstituted With2-C16alkylene, substituted or unsubstituted With2-C16albaniles, substituted or unsubstituted C1-C12alkyl(aralen) or substituted or unsubstituted aryl (C1-C12alkylen), and

R6and R7independently mean hydrogen, oxygen or With1-C4alkyl,

his donate the first salt, hydrate and alcohol MES.

First of all the agent for delivery is chosen from the group consisting of 5-CNAC, SNAD and SNAC and their pharmaceutically acceptable salts, especially disodium salt of 5-CNAC, disodium salt of SNAD and disodium salt of SNAC.

In yet another embodiment of the present invention, the agent for delivery of the present invention is used in finely powdered form, preferably with an average particle size of less than 40, more preferably less than 20, even more preferably less than 10 microns.

In another embodiment of the present invention use calcitonin in the composition of the conjugate with the polymer molecule.

In yet another embodiment, calcitonin is used in a mixture with at least one pharmaceutically acceptable agent to reduce the pH at least one amplifier, absorption and intersolubility the floor.

First of all, calcitonin is used in therapeutically effective amounts in free form or in salt form in an amount of from about 0.4 mg to 2.5 mg for administration to the patient, for example a person weighing, for example, 70 kg, in a mixture with the agent for delivery of calcitonin. More preferably, in the method according to the present invention using a dose of about 0.8 mg, for example from 0.6 to 1.2 mg, more preferably use a dose of less than 1 mg, but more than 0.4 mg, for example, approximately 0.6-0.8 mg, for example, 0.8 mg, n is the most preferred dose of about 0.8 mg, for example, from 0.8 to 1.2 mg of the dose administered in the form of single or multiple forms, primarily once a day or, in another embodiment, two times a day.

In yet another embodiment, the pharmaceutical composition intended for oral administration in the treatment or prevention of rheumatoid arthritis or related conditions in patients in need of such treatment, involves, first of all, calcitonin salmon, eel (Asu 1-7) or, more preferably calcitonin salmon in free form or in salt form and the agent for delivery of calcitonin in a mixture with one or more pharmaceutically acceptable diluents or carriers.

First of all, the present invention relates to pharmaceutical compositions of the present invention and, as indicated above, the agent for delivery mean compound of the formula I

where

R1, R2, R3and R4independently mean hydrogen, -OH, -NR6R7, halogen, C1-C4alkyl or C1-C4alkoxy,

R5means substituted or unsubstituted With2-C16alkylene, substituted or unsubstituted With2-C16albaniles, substituted or unsubstituted With1-C12alkyl(aralen) or substituted or unsubstituted aryl(C1-C12alkylen), and

R6and R7not avisio mean hydrogen, the oxygen or With the1-C4alkyl, its disodium salt, hydrate and alcohol solvate.

More preferably the present invention relates to pharmaceutical compositions in which, as indicated above, the agent for delivery is chosen from the group consisting of 5-CNAC, SNAD and SNAC and their pharmaceutically acceptable salts, especially disodium salt of 5-CNAC, SNAD and SNAC.

In yet another embodiment, the agent for delivery of the present invention is used in finely powdered form, preferably with an average particle size of less than 40, more preferably less than 20, even more preferably less than 10 microns.

In another embodiment, the present invention features a pharmaceutical composition for oral administration comprising a therapeutically effective amount of calcitonin in the composition of the conjugate with the polymer molecule.

In yet another embodiment, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of calcitonin, at least one pharmaceutically acceptable agent to reduce the pH, at least one amplifier, absorption and intersolubility floor.

In another embodiment, the present invention relates to pharmaceutical compositions for prevention or treatment of rheumatoid arthritis or related conditions in a patient in need of such Les is the situation, comprising a therapeutically effective amount of calcitonin in free form or in salt form in a dose of from about 0.4 mg to about 2.5 mg of the mixture with the agent for delivery of calcitonin. More preferably, the pharmaceutical composition comprises calcitonin dose of about 0.8 mg, for example from 0.6 to 1.2 mg, more preferably in quantities of less than 1 mg, but more than 0.4 mg, for example, at a dose of 0.6 to 0.8 mg, for example, 0.8 mg, most preferably in amount of about 0.8 mg, for example, from 0.8 to 1.2 mg of the dose administered in the form of a single or multiple dosage forms, preferably once a day, or, in another embodiment, two times a day.

In yet another embodiment, the present invention relates to a pharmaceutical combination for use in the treatment or prevention of rheumatoid arthritis in a patient in need of such treatment, including:

A. the first agent, which is a calcitonin, first of all, calcitonin salmon, eel (Asu 1-7) or, more preferably, calcitonin salmon, in a dose of from about 0.4 to 2.5 mg, and

B. joint agent selected from the group comprising calcitonin salmon, eel (Asu 1-7) or person, analogue or derivative of calcitonin, inhibitors SOH-2, for example, lumiracoxib (Prexige®), celecoxib (Celebrex®), rofecoksib (Vioxx®), valdecoxib (Bextra®), e is oritaxim (Arcoxia®), or a mixture of inhibitors of MOR-1 and MOR-2, for example, diclofenac, etanercept (Enbrel), anesthetic agent (e.g., aspirin, paracetamol), agents, bone-forming, and agents against resorption.

The term "oral"used in this context, includes any oral delivery (e.g., buccal and sublingual).

The term "agent for delivery"used in this context, refers to compounds native or molecules vehicles used for oral delivery of therapeutic agents. The term "agent for delivery" in this context is used interchangeably with the term "media".

The term "therapeutically effective amount" of calcitonin in the composition of the oral dosage forms of the present invention means the amount of calcitonin, sufficient to achieve a clinically meaningful improvement associated with rheumatoid arthritis, human or animal, for example, suppression of inflammation or swelling of the joints, suppression, suspension and/or treatment of erosion and destruction of cartilage and bone tissue and/or decrease pain, or amount, sufficient to prevent the development of these conditions.

The term "patient"used in the present invention, means a patient in need of treatment or prevention of rheumatoid arthritis, or any, of the decree is hydrated in paragraph 1.1-2.3 above, and patient means a mammal, such as rodents, cattle, pigs, dogs, cats and primates, especially humans.

The term "pharmaceutical combination"used in this context, means the product that is obtained by mixing or combining multiple active ingredient and includes both fixed and non-fixed combinations of the active ingredients.

The term "fixed combination" means that the active ingredients, for example, calcitonin salmon, and the co-agent is administered to a patient simultaneously in the form of a single drug or dosage form.

The term "non-fixed combination" means that the active ingredients, for example, calcitonin salmon, and the co-agent is administered to the patient in various dosage forms simultaneously or sequentially without time limits, and this introduction provides therapeutically effective levels of both compounds in the body of the patient.

The term "standard oral dosage form" refers to a discrete form suitable for administration to a human or animal, packaged individually as is known in the art. In the present invention means that the dosage form according to the present invention includes a therapeutically effective amount calcite is on, and the agent for delivery optionally includes one or more standard dosage form (e.g. tablet or capsule), which provide a therapeutic effect.

The term "multiple dose" means that the pharmaceutical composition of the present invention, comprising a therapeutically effective amount of calcitonin and agent for delivery, primarily in the form of standard oral dosage form is administered to a human or animal in at least two doses in accordance with the interval of doses suitable for this composition.

The term "single dose" means that the pharmaceutical composition of the present invention, comprising a therapeutically effective amount of calcitonin and agent for delivery, primarily in the form of standard oral dosage form, administered to a person or animal in a single dose.

Preferably calcitonin, such as calcitonin salmon in free form or in pharmaceutically acceptable salt is administered together with a protease inhibitor such as an inhibitor of cathepsin, such as an inhibitor of cathepsin K.

The applicability of calcitonin, for example, calcitonin salmon, in free form or in salt form comprising pharmaceutically acceptable oral dosage form intended for administration via any of the ways is s, described in paragraph 1.1-1.10, or any pharmaceutical composition as described above, in this context, can be illustrated using animal models and clinical trials.

In one embodiment, the pharmaceutical composition for use in oral form for the treatment or prevention of rheumatoid arthritis or related conditions in patients in need of such treatment, includes calcitonin, first of all, calcitonin salmon in free form or in salt form, the agent for delivery of calcitonin and do not necessarily suitable farmatsevticheskii acceptable excipient.

Calcitonin is any calcitonin, including natural, synthetic, or recombinant, and in addition, calcitonin derivative, such as calcitonin, eel 1.7 to Asu. Songs include one kind of calcitonin or a combination of two or more calcitonine. The preferred form of calcitonin is a synthetic calcitonin salmon.

Various kinds of calcitonin, including calcitonin salmon, porpoises and sea eel, are commercial drugs or synthesized by known methods.

Dosage forms for oral maintenance include tablets, capsules, pills, plate, granules, liquids for oral administration such as syrups, suspensions, emulsions and powders to obtain Leka is the only solutions or suspensions.

According to the present invention, therapeutically effective doses are from about 0.4 mg/day to about 2.5 mg/day, preferably from about 0.6 mg/day to about 1.2 mg/day, more preferably from about 0.6 mg/day to about 0.8 mg/day or from about 0.8 mg/day to about 1.2 mg/day, in single or multiple doses, primarily one or two times per day for a patient, such as a person, for example a person weighing 70 kg

If the pharmacologically active agent is calcitonin salmon, suitable dose varies depending on, for example, from patient to patient and the nature and severity of the condition to be treated. First of all, the dosage of the compounds of the present invention for any patient depends on various factors such as age, gender, body weight, General health, diet, individual response of the patient, time of administration, the severity of the disease to be treated, the activity of the applied compounds, pharmaceutical form, route of administration, and concomitant treatment. A therapeutically effective amount for a particular case is determined experimentally by the attending physician or therapist.

However, in General satisfactory results are achieved with systemically is the introduction of daily doses from about 0.5 μg/kg to about 10 μg/kg body weight, preferably from about 1 μg/kg to about 6 mg/kg of body weight. For the average person weighing 70 kg, a daily dose of from about 0,035 to 0.7 mg, preferably from about 0.07 mg to about 0,42 mg

In another embodiment, a therapeutically effective dose of calcitonin is from about 0.035 mg/day to about 0.7 mg/day, primarily from approximately 0.07 mg/day to about 0,42 mg/day, most preferably from about 0,42 mg/day to about 0.7 mg/day.

Pharmaceutically acceptable inactive excipients used to obtain oral formulations of calcitonin include polymers and inactive compounds, for example, used as an auxiliary connections for the processing or production of solid oral dosage forms of the present invention, or as agents for release of the drug from the solid oral composition in the gastrointestinal tract. Pharmaceutically inactive ingredients mentioned above, for example, does not necessarily include crospovidone and povidone, which include any crospovidone and povidone. Crosspovidone is a synthetic crosslinked homopolymer N-vinyl-2-pyrrolidone, the so-called 1-ethynyl-2-pyrrolidinone, with molecular weight of 1000000 or more. The commercial is ski crospovidone include Polyplasdone XL, Polyplasdone XL-10, Polyplasdone INF-10, manufactured by the company ISP, Kollidon CL, manufactured by BASF Corporation. The preferred crosspovidone is Polyplasdone XL. The povidone is a synthetic linear polymer, including direct group 1-vinyl-2-pyrrolidinone, with a molecular weight of from 2500 to 3000000. Commercial povidone include Kollidon K-30, Kollidon K-90F, manufactured by BASF Corporation, and Plasdone K-30 and Plasdone K-29/32, manufactured by ISP. As mentioned above, crospovidone and povidone are commercial products. In another embodiment, they are obtained by known methods. Crospovidone, povidone and their combination is usually included in the composition in an amount of from about 0.02 to about 50 wt.%, first of all, from approximately 0.5 to 50 wt.% calculated on the total weight of the pharmaceutical composition, preferably from about 2 to 25 wt.%, more preferably from 5 to 20 wt.%, most preferably 3 to 7 wt.% calculated on the total weight of the pharmaceutical composition.

Agents for delivery, used for obtaining compositions, for example, oral composition, are any agents for the delivery of specific pharmacologically active agent. Suitable agents for delivery include any modified amino acids described in the above-mentioned patent US 5866536, or any modified amino acids described in the above-mentioned patent US 5773647 or any of them to whom MINALI. The content of the above-mentioned US patents 5773647 and 5866536 included in this context as a reference. In addition, the agent for delivery is the disodium salt of any of the above amino acids, and ethanol-solvate and hydrate. Suitable compounds include the compounds of formula I

where

R1, R2, R3and R4independently mean hydrogen, -OH, -NR6R7, halogen, C1-C4alkyl or C1-C4alkoxy,

R5means substituted or unsubstituted With2-C16alkylene, substituted or unsubstituted With2-C16albaniles, substituted or unsubstituted C1-C12alkyl(aralen) or substituted or unsubstituted aryl(C1-C12alkylen), and

R6and R7independently mean hydrogen, oxygen or With1-C4alkyl, their hydrates and alcohol solvate. The compounds of formula I and their disodium salts and alcohol solvate and hydrate, as well as methods for their preparation are described in the application WO 00/059863.

Disodium salt is obtained from the ethanol solvate by evaporation or drying by known methods, you get anhydrous disodium salt. Drying is usually carried out at a temperature of from about 80 to about 120°C., preferably at from about 85 to about 90°C, n is andmore preferably at about 85°C. Stage drying is usually carried out at a pressure of 26 mm Hg or more. Anhydrous disodium salt typically includes less than 5 wt.% ethanol, preferably less than 2 wt.% ethanol per 100% by mass of the anhydrous disodium salt. Disodium salt of agent for delivery, in addition, receive when suspendirovanie agent for delivery in water and adding two molar equivalents of aqueous sodium hydroxide, sodium alkoxide, etc. Suitable alkoxides include sodium, without limitation, sodium methoxide, ethoxide sodium and mixtures thereof. Another way to obtain the disodium salt includes the interaction of agent for delivery with one molar equivalent of sodium hydroxide will get a disodium salt. Disodium salt is isolated in the form of a solid matter concentration of the solution of the disodium salt to a thick paste with distilled under vacuum. The resulting paste is dried in a vacuum Cabinet, you get a disodium salt of agent for delivery in the form of solids. The solid is isolated by drying aqueous solution of disodium salt in the dryer with the nozzle. The agent for delivery to get by known methods, for example, as described in patents US 5773647 and 5866536. Ethanol solvate as described in the application WO 00/059863 include, without limitation, molecular or the district complexes of molecules or ions of ethanol molecules or ions disodium salt agent for delivery. Usually ethanol solvate include approximately one molecule or ion of ethanol per molecule of disodium salt of agent for delivery. Ethanol solvate disodium salt agent for delivery obtained by dissolving agent for delivery in ethanol. Typically, 1 g of agent for delivery dissolved in from about 1 to 50 ml ethanol, or in General from about 2 to about 10 ml of ethanol. A solution of agent for delivery in ethanol then interacts with a molar excess of sodium salt, for example, monosodium salt, in respect of the agent for delivery, i.e. for each mol of agent for delivery to add more than one mole of cations of sodium, you get ethanol MES. Suitable monosodium salts include, without limitation, sodium hydroxide, sodium alkoxides such as sodium methoxide and ethoxide sodium, and any combination thereof. Preferably at least about two molar equivalent monosodium salt added to a solution of ethanol, i.e. for each mol of agent for delivery to add at least about two moles of sodium cations. In General the reaction is carried out at the boiling temperature of the mixture or below, for example, by CT. Ethanol MES then allocate by known techniques, such as concentration of the resulting suspension distillation in almost the situations conditions, cooling of the concentrate, and separating the solids by filtration. The obtained solid is dried in vacuum and get ethanol MES. The hydrate disodium salts of agents for delivery obtained by drying an ethanol solvate with the formation of the anhydrous disodium salt, as described above, and the hydration of anhydrous disodium salt. Preferably formed monohydrate disodium salt. Since the anhydrous disodium salt is very hygroscopic, the hydrate is formed under the action of moisture from the atmosphere. In General stage of hydration is carried out at a temperature from CT to approximately 50°C, preferably at temperatures from CT to approximately 30°C and at a relative humidity of the environment at least 50%. In another embodiment, the anhydrous disodium salt hydratious steam.

Preferred agents for delivery are N-(5-chlorosalicylic)-8-aminocaproic acid (5-CNAC), N-(10-[2-hydroxybenzoyl]amino)capric acid (SNAD), N-(8-[2-hydroxybenzoyl]amino)Caprylic acid (SNAC) and their pharmaceutically acceptable salts, preferably monosodium and disodium salts, ethanol solvate of sodium salts and monohydrate sodium salts and any combination of these compounds.

The most preferred agent for delivery is the sodium salt of 5-Save its monohydrate. Preferably the amount of the disodium salt is more than 90 wt.% calculated on the total weight of 5-CNAC in the composition.

The ratio of active ingredient/agent for delivery is approximately from 1:25 to 1:600, more preferably from 1:25 to 1:400, even more preferably from 1:200 to 1:300 and 1:400 to 1:600, respectively, the preferred ratio in the case of the composition sCT/5-CNAC is 0.5-1 mg sCT 200-300 mg disodium salt of 5-CNAC.

Agents for delivery 5 CNAC, SNAD and SNAC have a high solubility in water and almost completely, i.e. more than 90%, are absorbed in the gastrointestinal tract after ingestion in the form of finely ground or coarse particles. However, it has been unexpectedly found that when the composition is used finely ground form of one of the agents, carriers, pharmacologically active agent in the composition of the present compositions is more fully absorbed in the bloodstream. Finely ground form of the agent carrier, used for solid oral dosage forms of the present invention, means the agent carrier, which when added to a mixture of pharmacologically active agent and pharmaceutically inactive ingredients characterized by an average particle size less than 40 microns. Preferably the agent is a carrier of the present invention is used in finely izmelchennoy form in which the average particle size is less than 20 μm. More preferably the agent is a carrier of the present invention is used in finely powdered form, in which the average particle size is less than 10 μm. The agent-carrier in finely ground form of the present invention receives when it is grinding in the mill suitable for grinding pharmaceutical ingredients for grinding pharmaceutical ingredients and/or agent of the carrier to a fine and homogeneous mixture of particles. Examples of such mills include an Air Jet Mill Gem T® (Copley Scientific Ltd., Nottingham, UK). Fine agent-native alone or in mixture with any combination of fine ingredients of the present invention is then sieved, for example, through a sieve with the appropriate cells and separated only by passing through a sieve ingredients with the desired particle size for use in the present invention. The pharmaceutical compositions of the present invention typically include an effective amount of one or more agents for delivery, that is sufficient for delivery of the active agent and provide the desired effect. Usually the agent for delivery is contained in an amount of 2.5 wt.% to 99.4 wt.%, more preferably from 25 wt.% up to 50 wt.%.

Preferably calcitonin, for example, calcitonin the salmon in the free form or in salt form, delivered in the form of an oral pharmaceutical composition comprising calcitonin and agent for delivery of calcitonin. More preferably specified oral pharmaceutical composition includes an agent for service delivery selected from the group consisting of 5-CNAC, SNAD and SNAC. More preferably specified oral pharmaceutical composition includes an agent for service delivery selected from the group comprising disodium salt of 5-CNAC, disodium salt of SNAD and disodium salt of SNAC. Even more preferably specified oral pharmaceutical composition includes an agent for delivery in finely ground form.

Pharmaceutically acceptable oral form compositions of the present invention, furthermore, includes a diluent.

As a diluent can be used, for example Avicel PH 102 or 101. The diluent is up to 90 wt.% calculated on the total weight of the pharmaceutical composition or used to compensate for differences between the desired and the actual mass of the obtained pharmaceutical composition, which comprises, for example, up to 600 mg, for example, 500 mg. Preferably the binding agent is from 20 to 70 wt.% calculated on the total weight of the composition, for example, from 40 to 60 wt.%, for example, 50 wt.%. If the final weight of the pharmaceutical composition is 500 mg, the amount of diluent is example is from 100 mg to 350 mg

In a preferred embodiment of the present invention, the diluent is microcrystalline cellulose.

In another embodiment, a calcitonin delivered orally in a different form, as described in the applications and patents W0 94/26778, US 5359030, US 5438040, US 5681811, US 6191105, US 6309633, US 6380405, US 6436990, US 6458776 and US 6479692 (the contents of which are included in this description as references). Such oral compositions are mainly stable conjugates of polypeptides and proteins.

In a broad object of the present invention such forms for oral administration are related to covalent conjugated complexes of calcitonin in which calcitonin covalently linked to one or more molecules of a polymer comprising hydrophilic fragment, for example, linear polyalkyleneglycol, and in which the specified polymer, in addition, includes a lipophilic fragment. One object of these oral forms of delivery include physiologically active composition of calcitonin comprising a physiologically active peptide, covalently linked to a polymer comprising (1) a fragment of linear polyalkyleneglycol and (2) lipophilic fragment, in which a peptide fragment of linear polyalkyleneglycol and lipophilic fragment together form a conformation that increases resistance to enzymatic degradation in vivo physiological Akti the nogo peptide comprising a physiologically active composition of calcitonin compared with one physiologically active calcitonin (i.e. in unconjugated form without polymer). In another object such forms for oral administration include to physiologically active composition of calcitonin in the three-dimensional conformation, including physiologically active calcitonin, covalently associated with Polysorbate complex, which includes (1) a fragment of linear polyalkyleneglycol and (2) lipophilic fragment, in which the physiologically active calcitonin, a fragment of linear polyalkyleneglycol and lipophilic fragment form the following conformation: (a) lipophilic fragment is located on the surface of the three-dimensional conformation, and (b) increased resistance to enzymatic degradation in vivo physiologically active calcitonin in the composition, comprising a physiologically active calcitonin, compared with one physiologically active calcitonin. Another object such oral formulations for delivery refer to multiligand conjugated complexes calcitonin, including triglyceride as the main fragment, and bioactive calcitonin, covalently associated with triglyceride slice through polyalkyleneglycol group attached to the carbon atom triglyceride fragment, and at least one residue of a fatty acid covalently linked to a carbon atom triglyceride fragment directly sludge is through polyalkyleneglycol group. In this multiligand kongugirovannom complex calcitonin carbon atoms d and triglyceride bioactive fragment includes residues of fatty acids, covalently attached, either directly or through polyalkyleneglycol group. In another embodiment, the residue of a fatty acid covalently attached, either directly or through polyalkyleneglycol group to the carbon atoms a and d triglyceride balance, and bioactive calcitonin covalently linked to a carbon atom 13 triglyceride fragment directly or through a polyalkylene group. In this multiligand kongugirovannom complex calcitonin bioactive calcitonin preferably covalently linked to a modified fragment of triglycerides through an alkyl group, or alternatively through other suitable spacer elements of the groups included in the scope of the present invention. In this context, the suitability of the spacer elements of the group is determined by the steric and compositional parameters, as well as the purpose of the composition.

Another object such oral compositions belong to Polysorbate complex, including polysorbates balance, triglyceride fragments and functional groups, including:

(1) the balance of fatty acids and (2) a fragment of polyethylene glycol comprising covalently linked physiologically active residue, e.g. the measures physiologically active residue, covalently linked with a suitable functional group consisting of a fragment of peg.

Such a covalent bond is a straight line, for example, through the terminal hydroxyl group of polyethylene glycol, or in another embodiment, the physiologically active residue attached, for example, through a fragment of polyethylene glycol with protected terminal hydroxyl group of spacer elements group with a free carboxyl group, thus protected group of the polyethylene glycol contains carboxyl end group that can covalently attach physiologically active residue. Such oral formulations for delivery refer to stable, water-soluble, conjugated complexes calcitonin, including physiologically active calcitonin, covalently associated with physiologically compatible fragment of polyethylene glycol modified glycolipid balance. In such complex physiologically active calcitonin covalently linked to a physiologically compatible polyethylene glycol modified glycolipid balance, via a labile covalent bond with lateral balance of amino acids in the polypeptide composition. Physiologically compatible polyethylene glycol modified glycolipid balance, it is also preferable in the cancel Polysorbate, for example, Polysorbate comprising residues of esters of a fatty acid selected from the group comprising monopalmitate, dipalmitate, monolaurate, dilaurate, trilaureth, monooleate, dioleate, trioleate, monostearate, distearate and tristearate. In such complex physiologically compatible polyethylene glycol modified glycolipid balance also includes a polymer selected from the group including ethers and esters of polyethylene glycol and of fatty acids, and fatty acids, for example, chosen from the group comprising lauric, palmitic, oleic and stearic acids. In the above-mentioned physiologically active complex calcitonin as an example, includes a calcitonin selected from the group comprising insulin, calcitonin, ACTH, glucagon, somatostatin, somatotropin, somatomedin, parathyroid hormone, erythropoietin, hypothalamic factors, prolactin, thyroid-stimulating hormone, endorphins, enkephalins, vasopressin, opioids, non-natural, superoxide dismutase, interferon, asparaginase, arginase, argininemia, adenosine-diaminopimelate, trypsin, chymotrypsin and papain. Another object of the present invention relates to oral dosage forms for the treatment of lack of insulin, comprising a pharmaceutically acceptable carrier and a stable, water-soluble, konyagi is consistent complex of insulin, including insulin or proinsulin, covalently linked to a physiologically compatible polyethylene glycol modified glycolipid balance.

In addition, another oral dosage form that can be used in the present invention, as described in the application W0 97/33531, patents US 5912014 and US 608618 (included in this description by reference). Such oral formulations protect calcitonin from the action of an acid environment and digestive enzymes when passing through the stomach and the intestine and contribute to its penetration into the bloodstream. In blood calcitonin exerts a therapeutic effect. This oral form is, for example, the pharmaceutical composition for oral administration of calcitonin salmon, including: (A) a therapeutically effective amount of calcitonin salmon, (B) at least one pharmaceutically acceptable agent to reduce the pH, (B) at least one power absorption, which increases the bioavailability of calcitonin salmon and (G) intersolubility floor, with the specified agent to reduce the pH in the composition of this pharmaceutical composition is present in quantity, adding 10 ml of 0.1 M aqueous solution of sodium bicarbonate the pH value of the specified solution is reduced to a value of not more than 5.5. The pharmaceutical composition includes the ENT is resolubilize coverage in an amount not more than 20 wt.% based on the weight of the pharmaceutical composition excluding the weight of the specified coating. The above-described pharmaceutical composition comprises intersolubility coverage in an amount not more than 5-15 wt.% in the calculation of the mass of a specified pharmaceutical compositions except Intercollege coverage.

Oral pharmaceutical composition comprising calcitonin for treating rheumatoid arthritis, get in the form of capsules including soft gel capsules, tablets, microtablets, other solid oral dosage forms that get by known methods.

Solid pharmaceutical compositions of the present invention are obtained when grinding agent carrier or agent of the carrier in a mixture with any combination of additional ingredients of the present compositions to the formation of the finely ground particles. Finely chopped agent, carrier or agent carrier in a mixture with finely chopped ingredients of the present invention is then processed suitable ways, for example, by stirring a mixture of the active agent or more active agents, the agent for delivery, crosspovidone or povidone and other ingredients, and the mixture is filled capsules, or the mixture is pressed or formed into tablets. In addition, the solid dispersion receive by known methods with subsequent processing into tablets or capsules.

Pref is established following examples are presented to illustrate the present invention and are obvious to a person skilled in this field. These examples do not limit the scope of the present invention.

Examples

A. Examples of formulations

The example 1 Composition 1 (3 games)

Getting crushed 5-CNAC: large particles of 5-CNAC, intended for grinding, were placed in a jet mill, Air Jet Mill Gem T® Copley Scientific Ltd., Nottingham, UK)was used 80 ceramic runners with a diameter of 8 cm, rod No. 2, 6 outlet size of 0.5 mm, the raw materials were loaded manually at a rate of about 700 g/h of the coarse particles of 5-CNAC crushed and periodically size was controlled under the microscope, equipped with a ruler, before the formation of particles of the desired size. Crushed three different parties and received average particle size, for example, D50=6 μm, 35 μm and 46 μm. Each batch was sieved using a conical sieve mill (Quadro Comil, Quadro Engineering Incorporated 613 Colby Drive, Waterloo, Ontario, Canada N2V 1A1) with a conical sieve U10, 813 μm, round hammer, at a speed of 1500 rpm, the performance of approximately 150 kg/h

Part 1-3. The composition of the mixture of calcitonin salmon and 5-CNAC with different particle sizes

td align="center"> Finely chopped 5-CNAC
IngredientAmount (mg)Percentage (%)
Calcitonin salmon10,25
22857
Avicel PH 102®147of 36.75
Crosspovidone NF205
Magnesium stearate41
The total number of400100

The receiving part 1:

Three different batches of tablets were obtained using three different party finely chopped 5-CNAC as disodium salt, in one lot of tablets average particle size of disodium salt of 5-CNAC was 46 μm (party A), in the second game average particle size of disodium salt of 5-CNAC was 6 μm (the party), and the third party - 35 microns (party C).

Calcitonin salmon (0.50 g), previously sifted through a sieve with cell diameter of 40 μm, 57 g of finely powdered disodium salt of 5-CNAC, sifted through a sieve with cell diameter of 35 μm, and 10 g of Polyplasdone XL (crospovidone, NF, International Specialty Products, 1361 Alps Road, Wayne, New Jersey, 07470, USA) was mixed in a vessel with a volume of 500 ml and mixed in the turbula mixer (100 revolutions at a speed of 46 rpm). Then the vessel was added 57 g of finely powdered disodium salt of 5-CNAC, question what annoy through a sieve with cell diameter of 35 μm, and of 36.75 g of Avicel PH 102® and stirred (500 rpm at a speed of 46 rpm). Adding more of 36.75 g of Avicel PH 102® and stirred (100 rpm at a speed of 46 rpm). To the vessel was added magnesium stearate (2.0 g), sifted through a sieve with cell diameter of 35 μm, and was stirred for another 1 min at a speed of 46 rpm and the Mixture was pressed in a tablet press for Manesty tableting VV. The weight of the tablets was approximately 400 mg

Example 2 Compositions 2-3

In another embodiment, received the following structures:

Part 2:
Ingredient% partymg tablet
Recombinant0,120,6
calcitonin salmon
5-CNAC (I)0,24A1,2
5-CNAC (II)45,36b226,8
Avicel PH 101 (I)3A15A
Avicel PH 101 (II)44,9b224,9
Crosspovidone NF525
Aerosil 200 PH0,31,5
Magnesium stearate1,05
Total weight of tablets (mg)100500

Mass (a+b)specified for the disodium salt of 5-CNAC, corresponds to a total mass of 200 mg 5-CNAC in the form of the free acid.

Mass (a+b)specified for Avicel PH 101 (I) and (II)corresponds to the total mass of Avicel PH 101.

Part 3:
Ingredient% partymg tablet
Recombinant0,160,8
calcitonin salmon
5-CNAC (I)2,1A4,8A
5-CNAC (II)2,1b4,8b
5-CNAC (III) 41,4218,4
Avicel PH 101 (I)3A15A
Avicel PH 101 (II)44,9b224,7b
Crosspovidone525
Aerosil 200 PH0,31,5
Magnesium stearate1,05
Total weight of tablets (mg)100500

Mass (a+b+C)indicated for the disodium salt of 5-CNAC, corresponds to a total mass of 200 mg 5-CNAC in the form of the free acid.

Mass (a+b)specified for Avicel PH 101 (I) and (II)corresponds to the total mass of Avicel PH 101.

The above compositions were obtained in the same way as described in example 1. Some modifications of the methods described below.

1. Weighed 0.25 g sCT DS

2. Was mixed with 5-CNAC (part I)

3. Sift the mixture obtained in stage 2, through sieve #60 (0.25 mm)

4. Washed sieve after stage 3 of 5-CNAC (part II)

5. Sift the Aerosil 200 Avicel PH and PHI01 (party I) through sieve #20 (0.85 mm)

6. Added Avicel PH101 (part II), prosea the hydrated material, received at stage 5, 5-CNAC (part III), sifted material obtained in stage 4, and crosspovidone in a diffusion mixer and stirred (150 games)

7. Sift the mixture through a sieve #20 (0.85 mm)

8. Sift magnesium stearate through a sieve #20 (0.85 mm) was added to the mixture obtained in stage 7

9. Mixed with lubricant (Mg stearate) (50 spins)

10. The mixture is extruded into round tablets with a diameter of 12 mm, FFBE embossed NVR/984.

Used the equipment described in example 1.

Example 3 Obtaining part 4

The above composition 2 was pressed into tablets of different hardness, using a press Manesty Beta press Fette 3090 with various pressing force. The obtained tablets with different dissolution profile was tested using rhesus on oral absorption of sCT. Tablets and their physical properties are described below in table 1 and 2.

Table 1
0.6 mg
Performance: 197600 table/h
Speed: 27 rpm
Force (kN)Mass (mg) Weight±CCAThickness (mm)Hardness (kilaguni)The hardness rangeTime raspados
t
The fragility
5,5500,580,584,955,885,7-6,130
6504,150,894,866,79the 5.7 to 7.7400,73
7,1503,681,014,69,418,3-10,42 min 30 sec-2 min 15 sec0,25
8499,680,69to 4.5210,249,8-10,93 min 40 sec-5 min 350,52
8,5502,04 0,934,4711,711,2-12,84 min 30 sec-5 min 460,25
9505,740,624,431211,7-12,66 min 15 sec-7 min 550,14
10,2504,80,57or 4.3113,74from 12.8 to 14.67 min 19 s-8 min 8

Table 2
0.8 mg
Performance: 329400 table./h Speed: 45 rpm
Force (kN)Mass (mg)Weight±CCAThickness (mm)Hardness (kiloton
you)
Range what zones hardness Time raspados
t
The fragility
5,1497,010,674,882,942,4-3,1201,1 (strong exfoliation)
6,4497,970,75of 4.664,223.7 to 4.730-350,38 (strong exfoliation)
7499,4914,55,264,6-6,01 min 10 s0,44
8496,660,574,436,51of 6.0 to 7.12 min 420,14
9,1497,560,55or 4.317,877,5-8,3 2 min 35 s-3 min 590,1
10503,160,714,25to 8.348-8,93 minutes and 40 seconds to 4 minutes 300,05
11,2503,210,664,189,65of 9.3 to 10.15 min 40 sec-6 min 550,03
12,1502,760,394,0511-5the 10.9 and 11.88 min 34

where

CCA - relative standard deviation

The dissolution profiles are shown below in figure 1.

Example 4 Induction and assessment of arthritis

Arthritis induced in rodents by systemic injection of collagen type II (S), is an experimental model, in many ways resembling rheumatoid arthritis, which is used to study the development of the disease (see Wooley R.N., Chapedelaine J.M., Immunogenetics of collagen-induced arthritis, Crit. Rev. Immunol., 8, cc.1-22 (1987) and Trentham D.E., Collagen arthritis as a relevant model for rheumatoid arthritis, Arth. Reum. 25, cc.911-916 (1982).

After immunization with purified S in complete Freund's adjuvant, in genetically susceptible rodent species develops arthritis, which is characterized by cellular and humoral immune response to S. Like rheumatoid arthritis induced by collagen arthritis (CIA) is characterized by rapid development of inflammation of the joints with subsequent erosion of cartilage and bone.

Highly purified bovine collagen type II (CIA) issued by the company Chondrex, Inc., 2607 151 st Place NE, Redmond, Washington 98052, USA.

Animals (male Lewis rats or mice DBA/1 J (H-2q) (Harlan Laboratories UK, Oxford, UK) aged 8-10 weeks were injected intradermally at the base of the tail with a single injection of 100 μg S, in the form of an emulsion in complete Freund's adjuvant (Difco, Detroit, MI, USA).

Animals are examined daily for signs of arthritis one week after immunization according to accepted clinical system, with each limb was assessed using a visual assessment of swelling and/or redness in the scores: 0=normal, 1=weak swelling and/or redness of the paw, 2=obvious swelling and redness of the entire limb, 2·5=marked swelling and redness, leading to loss of mobility of the legs, 3=ankylosis, as described in article Malfait A.M., D.M. Butler, D. H. Presky, etc., Blockade of IL-12 during the induction of collagen-induced arthritis (CIA) markedly attenuates the severity of the arthritis, Clin. Exp.Immunol. I'll cc.377-383 (1998).

Thus canevali each paw, the maximum possible score for each animal was 12. Hind legs examined daily for the presence of tumors with calipers (the minimum detectable change=0·1 mm, Kroeplin, Schluchtern, Germany).

In these tests rheumatoid arthritis was induced using a model of collagen-induced arthritis (CIA model) Lewis rats (8-9 weeks) with intradermal administration of porcine collagen type II.

In the group of animals with induced collagen group (CIA), which did not enter the drug, the disease was developed in the days 11-14.

In the group that was administered the drug, the rats twice a day was administered 50 mg/kg of 5-CNAC or 50 mg/kg of 5-CNAC+2 mg/kg of calcitonin.

The results are shown in figure 2, which shows the number of C-terminal telopeptide of collagen type II in serum (serum CTX-II) in % of control values at day 21 after injection of collagen for different groups (control group, the CIA and the CIA+calcitonin).

In the group of CIA disease was assessed by a significant increase in the concentration of C-terminal telopeptide of collagen type II in serum (serum TX-II) compared with the control group. Treatment with calcitonin reduces this rate by 33%.

1. A method of preventing or treating rheumatoid arthritis in a patient in need of such treatment, which for luchetta in the introduction oral indicated patient a therapeutically effective amount of calcitonin in free form or in salt form and the agent for delivery of calcitonin, where the agent for delivery is chosen from the group comprising N-(5-chlorosalicylic)-8-aminoacridone acid, N-(10-[2-hydroxybenzoyl]amino)dekanovu acid, N-(8-[2-hydroxybenzoyl]amino)Caprylic acid and their pharmaceutically acceptable salts.

2. The method according to claim 1, where the specified calcitonin is calcitonin salmon.

3. The method according to claim 1 or 2, where the agent delivery means disodium salt, alcoholic MES or hydrate.

4. The method according to claim 1 or 2, where the pharmaceutical composition comprises an agent for delivery selected from the group consisting of disodium salt of N-(5-chlorosalicylic)-8-aminoacyl, disodium salt of N-(10-[2-hydroxybenzoyl] amino)decanoas acid and disodium salt of N-(8-[2-hydroxybenzoyl]amino)Caprylic acid.

5. The method according to claim 1 or 2 where the specified pharmaceutical composition includes an agent for delivery in micronized form.

6. The method according to claim 5, where the specified agent for delivery in micronized form is characterized by an average particle size less than 20 microns.

7. The method according to claim 1 or 2, where the number of calcitonin in free form or in salt form is from 0.6 mg to 1.2 mg

8. The method according to claim 5, where the number of calcitonin in free form or in salt form is from 0.6 mg to 1.2 mg



 

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SUBSTANCE: invention relates to compounds of formula (I) given below or pharmaceutically acceptable salts thereof:

[where: each of X, Y, Z and W independently denotes a methane group which optionally contains substitutes selected from a group of substitutes α, or a nitrogen atom (except when all elements X, Y, Z and W denote a methane group which optionally contain substitutes selected from the group of substitutes α); A denotes -(C(R3)(R4))m1-; B denotes -O-; D denotes -C(O)-; m1 equals 0; Q denotes a methane group or a nitrogen atom; R denotes a group of formula (II)

, where R6 denotes a lower alkyl group; R7 and R8, together with the nitrogen atom with which they are bonded, form a 5-6-member nitrogen-containing aliphatic heterocyclic group; and where the group of substitutes α includes the following substitutes. Group of substitutes α: halogen atom, hydroxyl group, lower alkyl group, alkoxyl group (said group can be substituted with a cycloalkyl group), amino group, mono- or disubstituted lower alkylamino group, aryl group (said group can be substituted with a halogen atom, a -SO2CH3 group), aryloxy group (said group can be substituted with a halogen atom), heteroaryl group, where 'heteroaryl group' denotes a 5- or 6-member monocyclic saturated or unsaturated group containing 1-2 heteroatoms selected from an oxygen atom or a nitrogen atom (said group can be substituted with an alkoxyl group, alkyl group). The invention also relates to a histamine 3 receptor antagonist, histamine 3 receptor inverse agonist, a prophylactic or medicinal agent, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having histamine H3 receptor antagonist or inverse agonist action.

15 cl, 57 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to indole-3-yl-carbonyl-spiro-piperidine derivatives which have an effect of Vla-receptor antagonists and are presented by Formula I: where a tail spiropiperidine group A and residual R1, R2 and R3 are such as specified in the patent claim.

EFFECT: higher efficiency of applying the compounds in drugs effective in dysmenorrhea, hypertension, chronic heart failure, inadequate vasopressin secretion, hepatic cirrhosis, nephrotic syndrome, obsessive-compulsive disorder, anxious and depressive disorders.

22 cl, 42 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology, hematology, and can be applied for reduction of spontaneous erythrocyte aggregation in case of arterial hypertension with metabolic syndrome. For this purpose administered are dosed static and dynamic physical activity, daily swimming for not less than 40 min. per day in the middle of the day, as well as lisinopril in dose 10 mg 1 time per day in the morning and methformin 500 mg 2 times per day. Physical activity includes morning hygienic gymnastics, therapeutic-preventive gymnastics and divided physical exercises during the day. Treatment course is 2 months.

EFFECT: combination of treatment methods makes it possible to reduce spontaneous erythrocyte aggregation, which assists prevention of thrombotic complications in said category of patients.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology and cardiology, and concerns reducing spontaneous erythrocyte aggregation (SEA) in arterial hypertension with impaired glucose tolerance.. That is ensured by the integrated treatment that involves the administration of lisinopril 10 mg once a day in the morning and metformin 500 mg twice a day for 2 months, as well as graduated static and dynamic physical activity, including daily swimming for at least 30 minutes a day.

EFFECT: complex of drug-induced and drug-free modalities ensure reducing the SEA for 2 months that in turn promotes normalised blood rheology and reduced risk of thrombotic complications in the case patients.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to gerontology and cardiology and can be used for reduction of pathologically increased biological age (BA) in patients with arterial hypertension (AH) with abdominal obesity (FO) and dyslipidemia. Essence of claimed method lies in the following: to patients administered is complex, that includes hypocaloric diet, calculated in kcal by formula: for women: 18-30 years old - (0.0621 × body weight, kg + 2.0357) × 240; 31-60 years old - (0.0342 × body weight, kg + 3.5377) × 240; over 60 years old - (0.0377 × body weight, kg + 2.7545) × 240; for men: 18-30 years old- (0.0630 × body weight, kg+ 2.8957) × 240; 31-60 years old - (0.0484 × body weight, kg + 3.6534) × 240; over 60 years old - (0.049 × body weight, kg + 2.4587) × 240. Also administered are rationally dosed static and dynamic physical loadings, including morning hygienic gymnastics, preventive medical gymnastics, fractional physical exercises during the day, daily swimming in swimming pool for not less than 60 minutes per day. Also introduced are medications simvastatin 10 mg 1 time before going to bed after meal and lisinopril 10 mg 1 time per day in the morning for not less than 7 weeks.

EFFECT: invention combines application of all components of complex allows to normalise BA within 7 weeks of treatment.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly the preparation fexofenadine for allergic diseases. The pharmaceutical composition contains an effective amount of fexofenadine as an active ingredient, and excipients - hydroxypropyl cellulose, a filler, desintegrant glidant, a solubiliser and stearic acid salt. The filler represents a combination of lactose and starch. As glidant, the composition contains colloidal silicon dioxide.

EFFECT: pharmaceutical composition is presented in the form of tablets and is characterised by a high degree of release of the active substance and storage stability.

7 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: what is offered is a solid dosage pharmaceutical composition containing a combination of acetylsalicylic acid and ethylmethyl hydroxypyridine malate and ethylmethyl hydroxypyridine succinate possessing antiaggregant, lipid-regulating and gastroprotective activities. What is shown is substantial prolongation of shelf life of the solid dosage form.

EFFECT: pharmacological and pharmacokinetic findings of the new composition make perspective in manufacturing of the solid dosage drugs for preventing and treating obesity, pathological conditions of the cardiovascular system, preventing ischemic disorders with manifested atherosclerosis, old infarction, ischemic stroke; peripheral artery disease.

10 tbl

FIELD: medicine.

SUBSTANCE: what is presented is a therapeutic agent possessing neuroprotective action in ischemic cerebral injury and hypoxia, representing magnesium 2-aminoethanesulfonate (magnesium taurinate). It has been shown that magnesium taurinate possesses high neuroprotective action; therapeutic application of magnesium 2-aminoethanesulfonate 50 mg/kg in cerebral ischemia caused by one-side occlusion of a left carotid, and prevents the developing ischemic cerebral injuries more effectively than if applying Picamilonum. There are also presented: solid dosage pharmaceutical composition on the basis of this compound in the form of tablets, capsules, powders, and a pharmaceutical composition for injections.

EFFECT: neuroprotective properties enable the presented pharmaceutical compositions of magnesium taurinate suggested to be used for preventing and treating ischemic cerebral injures.

6 cl, 4 tbl

FIELD: medicine.

SUBSTANCE: present invention refers to medicine and describes a method for preparing a tablet exhibiting antihypertensive activity containing a) an active substance containing valsartan 80 or 160 mg or its pharmaceutically acceptable salt, and hydrochlorothiazide (HCTZ) 12.5 or 25 mg; b) pharmaceutical acceptable additives suitable for preparing tablets by compression wherein said method involves the stages, I) grinding of the active substance which contains said valsartan and said hydrochlorothiazide, and pharmaceutically acceptable additives; II) compression of a mixture of the grinded active substance and additives with making a comprimate with said compression for making the comprimate requires compaction of the dry mixture of the grinded ingredients; III) transformation of the comprimate into a granulate having a particle size distribution 9 to 340 micron; and IV) compression of the granulate with preparing the tablet.

EFFECT: method provides preparing the tablet possessing intensified antihypertensive activity.

4 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, namely to a method for preparation of pharmaceutical compositions represented by multiparticles using a roller compactor. The method is especially suitable for production of minitablets without application of a tablet press. The specificity of the used roller compactor consists in the rollers having indentations or press-moulds on the surface. Minitablets are produced by way of pressing the mixture between the roller rotating in opposite directions with immediate formation of symmetric minitablets which renders unnecessary a separate stage of pressing with a tablet press.

EFFECT: new method for production of minitablets without application of a tablet press.

6 cl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an orally dispersed tablet containing: max. 15 wt % of a low-dose therapeutically active substance selected from domperidone, mequitazine, codeine (base) and loperamide hydrochloride, 55 wt % to 70 wt % of mannitol of particle size of 30 mcm to 300 mcm; min. 2 % of maltodextrine; 3.5 wt % to 8 wt % of sodium croscarmellose; 10 wt % to 20 wt % of microcrystalline cellulose; 0.5 wt % to 1.5 wt % of magnesium stearate; and 1 wt % to 5 wt % of a corrective (correctives) and sweetener (sweeteners). A tablet is presented in the form of a combination of internal and external phases. The internal phase contains said therapeutically active substance, mannitol, maltodextrine and approximately a half of sodium croscarmellose. The external phase contains approximately a half of sodium croscarmellose, microcrystalline cellulose, magnesium stearate, and also correctives and sweeteners. The tablets are applied for nausea and vomiting.

EFFECT: dispersed tablets under the invention are orally decomposed for 20-40 s, have low fragility and sufficient strength.

17 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: solid dosage form contains valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives and is presented in the form of a two-layer tablet. Quantitative proportions of valsartan, amlodipine and hydrochlorothiazide are selected from the following: 160 mg/12.5 mg/5 mg, 160 mg/12.5 mg/10 mg, 160 mg/25 mg/10 mg, 160 mg/25 mg/5 mg and 320 mg/25 mg/10 mg. Preferentially, amlodipine is used in the form of amlodipine besylate. The two-layer tablet can contain valsartan and hydrochlorothiazide in the first layer, and amlodipine in the second layer, or valsartan in the first layer, and amlodipine and hydrochlorothiazide in the second layer. Also, there are described methods for making a two-layer tablet.

EFFECT: two-layer tablet under the invention with the fixed combination of valsartan, amlodipine and hydrochlorothiazide have the biological properties equivalent to those of a free combination of said medical agents.

17 cl, 11 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutical industry, and deals with diuretic composition with delayed release, in which torasemide is an active substance.

EFFECT: compositions, corresponding to invention, are used to obtain possibility to avoid trouble-causing pressing urge to urinate, caused by conventional compositions with immediate release.

9 cl, 11 ex, 2 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns a method for preparing a dosage form of a hypolipidemic, hypoglycemic agent of thioctic (α-lipoic) acid. A mixture of thioctic acid, microcrystalline cellulose and lactose is wetted with hydroxypropyl methyl cellulose in the mixture of water and ethanol; the wetted mass is mixed, dried, granulated; the granulate is added with magnesium alumomethasilicate, primojel, magnesium and/or calcium stearate, sodium stearylfumarate, aerosil and/or talc; the tablets are pressed and coated with the film Opadry II. As a result, there are produced the coated tablets containing thioctic acid 300 mg and 600 mg as the active substance.

EFFECT: prepared drug preparation provides effective daily dosage - 600 mg/day for 1 - 2 intakes; the preparation is storage stable.

2 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and concerns a new pharmaceutical composition in a free-flowing form consisting of various microtablets with various ingredients with the microtablets having the same space form and the same weight. The invention also concerns a method for preparing said composition and applying it as a drug for treating and preventing diseases.

EFFECT: invention provides the composition showing uniform distribution of the active ingredients and easily dosed when making individual compositions.

8 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to pharmacy and medicine. Pharmaceutical composition includes mixture of: (a) active macromolecular substance; (b) aromatic alcohol, absoption amplifier, selected from propylgallate, butylated hydroxytotuol (BHT), butylated hydroxyanisole (BHA) and their analogues and derivatives, or their mixtures; and (c) biguanide or its pharmaceutically acceptable salt, capable of increasing solubility of aromatic alcohol, absorption amplifier, in water medium, where aromatic alcohol, absorption amplifier, is present in amount (by weight) greater or equal to amount of active substance. Application in pharmaceutical composition of aromatic alcohol, selected from propylgallate, BHT, BHA and their analogues and derivatives, together with biguanide or its pharmaceutically acceptable salt, capable of increasing solubility of aromatic alcohol in water medium, as amplifier of macromolecule absorption through intestine wall. Method of increasing absorption of active macromolecular substance and method of patient treatment include introduction of claimed composition to patient. Application of active macromolecular substance, selected from insulin, C-peptide, GLP-1 or their mixture; aromatic alcohol, absorption amplifier, selected from propylgallate, butylated hydroxytotuol (BHT), butylated hydroxyanisole (BHA) and their analogues and derivatives, or their mixtures; and biguanide or its pharmaceutically acceptable salt, capable of increasing solubility of aromatic alcohol, absorption amplifier, in water medium, in manufacturing medications for treatment of diabetes, osteoporosis, obesity, cancer, osteoarthritis.

EFFECT: group of inventions ensures facilitation of passage of peptides, proteins and other macromolecular substances through intestinal wall for improvements of their bioavailability.

27 cl, 3 tbl, 11 ex

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